HDL mimetics protect Alzheimer's patients carrying APOE ε4 from SARS-CoV-2 invasion

Ruodan Xu, Junwei Gao, Can Cao, Mingfei Shi, Yonghui Zhang, Shihao Hong, Shijie Guo, Menglin Chen, Ping Song, Gaoshuang Fu, Jing Li, Tengxiao Liang, Yingchun Miao, Lu Tang, Jinsheng Yang, Ning Li*, Mingdong Dong

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

Patients with Alzheimer's disease (AD) inheriting Apolipoprotein (APOE) ε4 are susceptible to COVID-19, but the underlying mechanism of how such a neurodegenerative disease promotes respiratory vulnerability to viral infections remains insufficiently understood. The uncovering of genetic basis of COVID-19 outcome holds the potential to establish disease models for therapeutic development. Here, using human iPSC-derived type II alveolar epithelial cells (hAECII) from AD patients with APOE ε4 and healthy individuals, we showed that AECII of AD had a greater level of SARS-CoV-2 invasion but not replication, along with increased expressions of viral receptor and co-receptors, while reduced pulmonary surfactant proteins. Since low serum HDL-C levels have been implicated in the onset of both AD and COVID-19, we further revealed that HDL mimetics, including 4 F dimeric peptide and its phospholipid conjugate pHDL, were effective in protecting AECII bearing APOE ε4 against SARS-CoV-2 invasion. In AD, concomitant with improved AD pathological phenotypes, HDL mimetics specifically restored the defective basal SP-D, a pulmonary innate immune lipoprotein that targets glycans of the spike protein to neutralize invading viruses. Moreover, HDL mimetics demonstrated strong SP-D-independent virucidal effects, which additionally restricted the entry of coronaviral particles into non-AD AECII models and lungs of human ACE2-transgenic mice in response to Alpha and Omicron variants of SARS-CoV-2. Our work offers critical insights into the respiratory sensitivity of AD patients carrying APOE ε4 to viral infection and repurpose HDL-based therapeutics as potential preventive interventions in respiratory viral pandemics.

Original languageEnglish
Article number102051
JournalNano Today
Volume53
Number of pages18
ISSN1748-0132
DOIs
Publication statusPublished - Dec 2023

Keywords

  • Alzheimer's disease
  • APOE
  • COVID-19
  • HDL mimetics
  • SARS-CoV-2
  • Surfactant protein D

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